Melanocortins, peptide products resulting from post-translational processing of pro-opiomelanocortin (POMC), are known to have a broad array of physiological activities, including affects on behavior, learning, memory, control of the cardiovascular system, analgesia, thermoregulation, and the release of other neurohumoral agents including prolactin, luetinizing hormone, and biogenic amines (De Weid et al. Methods Achiev. Exp. Pathol.(1991) 15:167-199; De Weid et al. Physiol. Rev. (1982) 62:977-1059; Gruber, K. A. et al. Am. J. Physiol. (1989) 257:R681-R694; Murphy et al. Science (1980) 210:1247-1249; Murphy et al. Science (1983) 221:192-193; Ellerkmann, E. et al. Endocrinol. (1992) 130:133-138; Versteeg, D. H. G. et al. Life Sci. (1986) 835-840). Natural melanocortins include the different types of melanocyte stimulating hormone (α-MSH, P-MSH, y-MSH) and ACTH. Of these, α-MSH and ACTH are considered to be the main endogenous melanocortins. Physiological effects of melanocortins are mediated through the melanocortin receptors (MC-Rs), a subfamily of seven-transmembrane G-protein coupled receptors. Five different receptor subtypes (MC1-R to MC5-R) have been identified to date. While other receptor family members are expressed in various peripheral tissues, MC3-R and MC4-R are localized predominantly in the CNS and brain.
The melanocortin-4 receptor (MC4-R) was identified as a melanocortin receptor subtype which may participate in various physiological functions, including modulating the flow of visual and sensory information, coordinating aspects of somatomotor control, and/or participating in the modulation of autonomic outflow to the heart. K. G. Mountloy et al, Science, 257.1248-125 (1992). Significantly, inactivation of this receptor by gene targeting has resulted in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycernia. D. Huszar et al., Cell, 88: 131-41 (1997). Additional studies have further supported a role for MC4-R in metabolic regulation: MC4-R is located throughout the brain, primarily in the satiety control regions of the hypothalamus; satiety and energy homeostasis have been shown to be regulated by MC4-R; and agonism of MC4-R leads to decreased food intake and lower body weight. Pritchard, L E et al Endocrin 172: 411-412 (2002); Cummings, D E and Schwartz, M W Nature Genetics 26:8-9 (2000); and Harrold, J A et al Diabetes 48: 267-271 (1999). Still further support of a role in weight regulation is provided in recent studies demonstrating that antagonism of MC4-R leads to increased feeding and weight gain, and MC4-R knockout mice resist cachexia induced by tumor growth Wisse, B E et al Endocrinology 142: 3292-3301 (2001); and Marks, D L et al Cancer research 61: 1432-1438 (2001).
MC4-R has also been implicated in processes involved in additional disease states, including cardiovascular disorders, neuronal injuries or disorders, inflammation, fever, erectile disorders, and sexual behavior disorders. M. E. Hadley and C. Haskell-Luevano, Ann. N.Y. Acad. Sci., 885:1 (1999); Vrinten D H, et al. J Neurosci, 20:8131-7 (2000); Dunbar J C, and Lu H, Peptides, 21:211-7 (2000); Huang Q H, et al. Am J Physiol 276:R864-71 (1999); and Van der Ploeg L H, et al. Proc Natl Acad Sci USA 99:11381-6 (2002).